Diseases caused by chronic virus infections are a significant worldwide health problem. CD8+ T cells fail to eliminate infections, such as HIV and HCV, which establish persistence with pathological consequences. T cells specific for these viruses are rendered ineffectual due to several suppression mechanisms. Despite the clear importance of T cells in the control of these virus infections, recent data indicate that natural killer (NK) cells also contribute to virus control or pathogenesis. Genetic polymorphisms within genes that regulate NK cell receptors are associated with HCV resolution. We use an established mouse model of T cell exhaustion that accurately reflects how human T cells undergo functional inactivation following persisting infection. We found a new mechanism that contributes to T cell exhaustion. NK cells subdue virus-specific CD8+ T cell responses in mice that are given a strain of lymphocytic choriomeningitis virus (LCMV) that disseminates widely and establishes persistence. Eliminating NK cells in infected mice improves virus-specific T cell function and number and vastly expedites viral clearance. We wish to better understand how NK cells restrain T cell responses in the context of persisting virus infection and understand the wider immunoregulatory functions of NK cells. Our preliminary data show that antigen presenting cells (APC) from NK-depleted mice are superior to APCs from NK cell-replete mice. Our central hypothesis is that during disseminating virus infection, elevated levels of interferon activate NK cells to inhibit or deplete APCs, which leads to T cell exhaustion and limited virus control. The objectives of Aim1 are to determine whether NK cell inhibition of T cell responses is governed by interferon signaling in mice that are exposed to acute or persisting LCMV infection. The in vivo activity of wildtype NK cells will be compared to those that are deficient in interfero-receptors. The objectives of Aim2 are to examine whether NK cells eliminate APCs or express suppressive cytokines that impair T cells or the stimulatory functions of APCs. The objectives of Aim3 are to determine whether NK cells inhibit memory T cell and B cell responses. The objectives of Aim4 are to explore whether memory NK cells persist to influence long-term immune responses. Overall, this project concerns the basic immunobiology of persisting virus infections. These efforts will support a long-term endeavor to explore the links between innate sensing of infection and T cell fate determination. These goals are relevant to improving the design of vaccines and therapeutics to prevent T cell exhaustion and sustain protective immune respones, which is a stated mission of the NIH, NIAID. Information gleaned from this project may translate beyond infection immunology to tumor immunology, where T cell exhaustion is a significant hurdle to successful T cell immunotherapies.